1. Technical Field
The present invention relates to compositions that interfere with the function of Tumor Necrosis Factor Alpha (TNF-xcex1) for use as therapeutics and diagnostics.
2. Background Art
Cytokines are peptide/protein immunomodulators that are produced by activated immune cells including thymus-derived T lymphocytes (T-cells), B lymphocytes and monocyte/macrophages. The cytokines include interleukins (IL-1 through IL-18), colony stimulating factors (CSFs) for granulocytes and/or macrophages (CSF-G, CSF-M, CSF-GM), tumor necrosis factors (TNFs xcex1 and xcex2), and interferons (IFN xcex1, xcex2 and xcex3). There is a large body of evidence currently available which supports the roles of IL-1 and TNF as major mediators of the systemic response to diseases such as sepsis and as activators of the remaining members of the cytokine cascade (Dinarello et al., 1993).
More specifically, tumor necrosis factor (TNF)-xcex1 has a broad range of effects on numerous different cell types throughout the body. It induces proliferation in some cell types, activation in other cell types, and release of other cytokines in some cell types. In many pathologic conditions, including inflammatory diseases such as arthritis, inflammatory bowel diseases, and dermatologic disorders, TNF-xcex1 is felt to be a major or the major cytokine responsible for inducing the inflammatory changes. TNF-xcex1 also may be involved in the survival and proliferation of some malignant cell types. Therefore, it is of considerable interest and potential clinical significance to identify compounds that interfere with the function of TNF-xcex1. Currently, soluble TNF receptors and antibodies to TNF-xcex1 are being used clinically and in clinical studies to attempt to compete for TNF-xcex1 binding, so as to prevent binding of TNF-xcex1 to cellular TNF receptors, which in turn should prevent activation of the receptors on inflammatory cells and prevent and possibly reverse the inflammatory changes that occur in certain types of patients with arthritis.
It would therefore be beneficial to find alternative means to inhibit TNF-xcex1 function, particularly discovery of small peptides that could bind to TNF receptors and interfere with the ability of TNF-xcex1 to bind to and activate cellular TNF-xcex1 receptors. Such molecules are very useful in research studies in vitro. However, more importantly, these molecules have significant clinical usefulness in treating a broad range of inflammatory conditions, arthritis, and cancers.
According to the present invention, there is provided a method of inhibiting TNF-xcex1 from binding to TNF receptors by administering an effective amount of an inhibitory peptide. Also provided is a method of inhibiting TNF-xcex1 functions by administering an effective amount of an inhibitory peptide. There is also provided a peptide which has TNF-xcex1 inhibitory properties. Also provided is a method of inhibiting TNF-xcex1 binding to TNF receptors by administering an effective amount of a peptide having the amino acid sequence shown in SEQ ID No. 1,2,3,4, wherein the peptides can be administered either singly or in combination.